Low Glucose Metabolism During Brain Stimulation in

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PIETRINI, GLUCOSE Am J Psychiatry DANI, METABOLISM FUREY, 154:8, August ET IN AL. DOWN’S 1997 SYNDROME

Low Glucose Metabolism During Brain Stimulation in Older Down’s Syndrome Subjects at Risk for Alzheimer’s Disease Prior to Dementia Pietro Pietrini, M.D., Ph.D., Alessio Dani, M.D., Maura L. Furey, Ph.D., Gene E. Alexander, Ph.D., Ulderico Freo, M.D., Cheryl L. Grady, Ph.D., Marc J. Mentis, M.D., David Mangot, B.S., Elliott W. Simon, Ph.D., Barry Horwitz, Ph.D., James V. Haxby, Ph.D., and Mark B. Schapiro, M.D.

Objective: Down’s syndrome is characterized by the genetically programmed accumulation of substantial Alzheimer’s disease neuropathology after age 40 and the development of early dementia years later, providing a unique human model to investigate the preclinical phases of Alzheimer’s disease. Older nondemented adults with Down’s syndrome show normal rates of regional cerebral glucose metabolism at rest before the onset of dementia, indicating that their neurons maintain function at rest. The authors hypothesized that an audiovisual stimulation paradigm, acting as a stress test, would reveal abnormalities in cerebral glucose metabolism before dementia in the neocortical parietal and temporal areas most vulnerable to Alzheimer’s disease. Method: Regional cerebral glucose metabolism was assessed by means of positron emission tomography (PET) with [18F]fluorodeoxyglucose in eight younger (mean age=35 years, SD=2) and eight older (mean age=50, SD=7) healthy, nondemented adults with trisomy 21 Down’s syndrome. PET scans were performed at rest and during audiovisual stimulation in the same scanning session. Levels of general intellectual functioning and compliance were similar in the two groups. Results: At rest the two groups showed no difference in glucose metabolism in any cerebral region. In contrast, during audiovisual stimulation the older subjects with Down’s syndrome had significantly lower glucose metabolic rates in the parietal and temporal cortical areas. Conclusions: Abnormalities in cerebral metabolism during stimulation appeared in the first cortical regions typically affected in Alzheimer’s disease. These results indicate that a stress test paradigm can detect metabolic abnormalities in the preclinical stages of Alzheimer’s disease despite normal cerebral metabolism at rest. (Am J Psychiatry 1997; 154:1063–1069)

D

own’s syndrome, or trisomy 21, is a genetic disorder in which an extra portion of chromosome 21 (including the Aβ-amyloid precursor protein gene) Preliminary data presented as an abstract at the 10th annual meeting of the Italian Society of Neuropsychopharmacology, Venice, Italy, Sept. 27–29, 1995, and at the 24th annual meeting of the Child Neurology Society, Baltimore, Oct. 24–28, 1995. Received Aug. 14, 1996; revision received Jan. 14, 1997; accepted Jan. 17, 1997. From the Laboratory of Neurosciences, National Institute on Aging, and the Elwyn Institute, Elwyn, Pa. Address reprint requests to Dr. Pietrini, Laboratory of Neurosciences, National Institute on Aging, NIH, Rm. 6C414, Bldg. 10, 9000 Rockville Pike, Bethesda, MD 20892; [email protected] (e-mail). Supported in part by a Young Investigator Grant from the National Alliance for Research on Schizophrenia and Depression to Dr. Dani and by the 1995 Italian Society for Neuropsychopharmacology Award to Dr. Pietrini. The authors thank the Laboratory of Neurosciences nursing staff, the NIH PET technicians, R. Carson and J. Ma. Maisog for implementing the double FDG injection technique, P. Herscovitch for organizing the NIH PET program, and P. Nichelli and E. Picano for reviewing this manuscript.

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causes all subjects with Down’s syndrome over the age of 40 years to show some degree of neuropathological and neurochemical abnormalities postmortem that are indistinguishable from those seen in Alzheimer’s disease (1, 2). Cognitive dysfunction and dementia are increasingly more common with aging, and 75% of persons with Down’s syndrome over age 60 are demented (3, 4). Thus, Down’s syndrome is a unique human model with which to study the preclinical stages of Alzheimer’s disease and transition to dementia (5, 6). Longitudinal neuropsychological evaluations of nonmemory cognitive functions showed two stages of cognitive decline in Down’s syndrome: a stable phase of at least 7 years preceding dementia and a subsequent period of linear decline, coincident with the onset of dementia (3, 7). Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) is a well-established in vivo technique for measuring rates of regional cerebral glucose metabolism in humans; these rates primarily are

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TABLE 1. Neuropsychological Status of Younger and Older Adults With Down’s Syndrome Younger Adults (N=8)

Older Adults (N=8)

Variable

Mean SD

Mean SD

Age (years) Stanford-Binet Intelligence Scale (11) mental age (years) Peabody Picture Vocabulary Test (12) age (years) Down’s Syndrome Mental Status Examination (13) score Recent memory score (3)a Immediate memory span score (3) Language score (3) Visuospatial construction score (3)

35 6.0 7.4 55.9 29.4 3.0 48.0 24.6

50 5.1 5.1 48.9 25.0 2.3 41.4 18.4

2 1.5 2.7 8.9 2.9 0.8 9.3 4.8

7 1.9 3.3 7.3 7.4 0.9 9.2 8.3

Analysis (df=14) t

p

–5.8 0.0001 1.0 n.s. 1.5 n.s. 1.8 n.s. 1.6 n.s. 1.5 n.s. 1.4 n.s. 1.8 n.s.

stress test, would reveal abnormalities in regional cerebral glucose metabolism in the neocortical areas most vulnerable to Alzheimer’s disease, including the parietal and temporal regions, before the onset of dementia. METHOD Subjects

aTotal

score from three memory tests: a subtest of the Down’s Syndrome Mental Status Examination (13), the Hidden Object Memory Test (13), and the Recognition Memory for Designs (13).

an index of synaptic function. Previous cross-sectional PET-FDG studies showed that regional cerebral glucose metabolism measured at rest (i.e., with the subjects’ eyes patched and ears plugged) did not differ between young adults with Down’s syndrome and age-matched comparison subjects (8) or between young and older nondemented subjects with Down’s syndrome (5). In contrast, older demented adults with Down’s syndrome showed lower than normal rates of absolute glucose metabolism in the temporal and parietal association neocortical areas (5), similar to the pattern seen in Alzheimer’s disease (9). A longitudinal study (7) demonstrated that older subjects with Down’s syndrome without memory or nonmemory cognitive impairment maintain regional cerebral glucose metabolism within the normal range for many years, although repeated measurements showed a progressive decline of glucose metabolism over time, with no change in nonmemory cognitive function in the subjects who later developed dementia. After the onset of dementia, both nonmemory cognitive function and cerebral glucose metabolism showed significant linear declines. The evidence that regional cerebral glucose metabolism at rest remains in the normal range in older adults with Down’s syndrome before the onset of clinical dementia or nonmemory cognitive impairment indicates that, despite an increasing accumulation of some degree of Alzheimer’s disease neuropathology in the neocortex, neurons in the resting state maintain the ability to produce energy and perform biochemical activities related to their survival. This view is consistent with in vitro data on postmortem brains of Alzheimer’s disease patients that demonstrated that neurons containing neurofibrillary tangles maintain some cytochrome oxidase activity (10). However, it is not known how such neurons would respond to extra stress during sensory or cognitive stimulation. We therefore expected that the progressive accumulation of Alzheimer’s disease neuropathology would result in an impairment of neuronal function before the appearance of clinical evidence of dementia in older Down’s syndrome subjects, who by definition are at risk for developing dementia. Specifically, we hypothesized that despite no abnormalities in cerebral glucose utilization at rest, an audiovisual stimulation paradigm, acting as a

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Brain metabolism was determined in 16 healthy subjects with trisomy 21 who were studied as part of an ongoing longitudinal study of cognition, brain structure, and brain function in adults with Down’s syndrome (5). The subjects included eight younger adults, aged 32 to 38 years, and eight older adults, aged 43 to 61 (table 1). All subjects were right-handed and lived in the community or in residential cottages. None of them had been institutionalized at any time during childhood or adulthood. Each subject was screened with a review of medical history, physical and neurological examinations, and psychiatric evaluation. Laboratory studies consisted of blood and urine tests, including routine blood cell counts, clotting studies, and serum chemistry; liver, renal, and thyroid function tests; HIV and VDRL tests; determination of cholesterol, triglyceride, antinuclear antibody, rheumatoid factor, vitamin B12, and folate levels; and chest radiography, electrocardiography, EEG, brain magnetic resonance imaging, and audiological and visual assessments, including testing of visual acuity, peripheral visual fields, pupillary function, eye fundus, and extraocular movements (5). Substantial past or present medical, neurological, or psychiatric illnesses (other than Down’s syndrome)—including hypertension; diabetes mellitus; malignancy; renal, hepatic, and cardiac disease; epilepsy; stroke; transient ischemic attack; head trauma with prolonged loss of consciousness; exposure to toxic substances; psychosis; substance abuse; and radiological evidence of intracranial pathology— were exclusionary criteria. Individuals with substantial ocular pathology (e.g., cataract, glaucoma), decreased visual fields, corrected visual acuity less than 20/30, or decreased hearing ability (other than reduced high-frequency discrimination) were excluded from the study, except for one subject each in the younger and older Down’s syndrome groups with additional low-frequency hearing loss. No subject was taking any medication apart from thyroid or vitamin B12 replacement. No subject had dementia according to previously validated standardized criteria for dementia in Down’s syndrome (14), which have been shown to have high interrater reliability among evaluating physicians (15). Further, in a multidisciplinary study group a consensus was reached on whether each subject had developed dementia. The younger and older subjects did not differ on mean mental age as measured by the Stanford-Binet Intelligence Scale (11), on memory, language, and visuospatial functions (3), or on score on the Down’s Syndrome Mental Status Examination Test (an overall measure of cognitive function) (13) (table 1). Informed written consent to participate in the study was signed by the holder of the durable power of attorney or the legal guardian after explanation of the procedures and risks involved. The research was conducted under NIH protocol 93-AG-139 as approved by the National Institute on Aging Institutional Review Board.

PET Procedure Technique. Regional cerebral glucose metabolism was measured by means of FDG and a high-resolution PET scanner (Scanditronix PC2048-15B; Uppsala, Sweden) with an axial resolution (full width at half maximum) of 6 mm. Radioactivity in the brain was simultaneously measured in 15 contiguous transaxial planes, with a slice-toslice separation of 6.5 mm, for a total axial field of 97.5 mm. The subjects were placed in the scanner in a quiet, dimly lit room with minimal background noise. A thermoplastic mask was used to maintain

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head position during scanning. To FIGURE 1. Mean Absolute Rates of Regional Cerebral Glucose Metabolism at Rest in Younger and correct for attenuation of radiation, Older Adults With Down’s Syndrome a multislice transmission scan was obtained at the same levels as the emission scans. Two sequential FDG studies were performed with each subject, one in the resting state and the other during audiovisual stimulation (to be described). Thirty-five minutes after the intravenous injection of 4.18 mCi of FDG, a 15-minute emission scan was obtained parallel to and 10–100 mm above the inferior orbitomeatal line. Arterial blood samples were collected for measurement of plasma radioactivity and glucose concentration. The values for glucose metabolism were calculated as milligrams of glucose per 100 g of brain tissue per minute, by using a modification (16) of the operational equation of Sokoloff et al. (17) and a value of 0.418 for the lumped constant (18). After completion of the first scan (total time, 50 minutes), a second bolus of 4.18 mCi of FDG was injected intravenously and a new scan was performed as just described. Experimental conditions. PET scans were obtained for each subject under two different conditions: while resting (eyes patched, ears plugged, minimal room noise) and while watching and listening to a color movie of interest to subjects with Down’s syndrome. All Statistical Analysis of the subjects were presented with the same movie for identical periods of time. The sound volume for the movie was adjusted to a Student’s t tests were used to compare the demographic and neurolevel comfortable for the individual subject. The movie was shown psychological measures for the younger and older subjects. Absolute to the subject on a screen positioned 55–60 cm from the subject’s cerebral glucose metabolic rates both at rest and during audiovisual eyes and tilted perpendicular to the line of sight. Before the experistimulation in the younger and older subjects were compared by using ment began, the subject’s ability to see the full screen was checked. a two-factor repeated measure analysis of variance (ANOVA), with To control for a possible order effect, the presentation of the two hemisphere as the repeated measure. Differences between groups in conditions was counterbalanced across subjects. The subjects were the magnitude of changes in glucose metabolism in response to stimuallowed to adjust to each condition for 2 minutes before isotope lation (value during stimulation minus value at rest) were tested by injection. using a two-factor repeated measures ANOVA, with hemisphere as

Data Analysis Regional levels of brain radioactivity were determined by using a template of 475 circular regions of interest 8 mm in diameter (48 mm2), derived from a PET scan of a healthy normal subject (adapted from the method of Kumar et al. [19]). Each of the 15 PET slices obtained in this individual was compared with an atlas of a human brain sectioned in the same plane as the PET scan (20). The regions of interest were spaced evenly throughout the cortical ribbon and centered in subcortical regions, such as the thalamus, caudate, and putamen. The template was placed over the corresponding PET slices for each subject and adjusted to fit the individual brains. Because the regions of interest could be individually moved, adjustments could be made for differences in head size and shape, such as brachycephaly, that occur in subjects with Down’s syndrome (8). The same template of regions of interest was used for the scans obtained under both experimental conditions. The values for glucose metabolism in the individual circular regions of interest were grouped into larger anatomical areas within the frontal, limbic, temporal, sensorimotor, parietal, and occipital cortexes, for a total of 29 regions, according to a standard neuroanatomic atlas (20). Data from the second scan were corrected for residual radioactivity from the first injection (FDG half-life, 118 minutes) by using a mathematical procedure (21).

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the repeated measure. Posterior cingulate and global gray matter glucose metabolism were compared by using t tests.

RESULTS

Compliance During the Experiment All subjects were able to complete the study and to comply with the requirements of each condition of the PET scan examination. The subjects provided correct answers to a standard set of questions regarding the content of the movie, indicating that they all attended to the movie. No subject was anxious during the scan, as assessed by a previously validated physician-administered global rating scale for anxiety (22). Rates of Cerebral Glucose Metabolism Resting. The younger and older subjects with Down’s syndrome showed no difference in global gray matter

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FIGURE 2. Mean Absolute Rates of Regional Cerebral Glucose Metabolism During Audiovisual Stimulation in Younger and Older Adults With Down’s Syndromea

DISCUSSION

These results demonstrate that older nondemented subjects with Down’s syndrome have significantly lower rates of regional cerebral glucose metabolism during audiovisual stimulation than do younger subjects with Down’s syndrome, despite similar values at rest. Thus, abnormal brain metabolism in subjects at risk for developing dementia can be revealed before the appearance of nonmemory cognitive decline or clinical dementia by increasing the functional demands on the brain. These metabolic abnormalities were most prominent in the parietal and the temporal neocortical areas, which are the regions most vulnerable to Alzheimer’s disease neuropathology (23) and the first to show abnormal brain metabolism in aRates for posterior cingulate and global gray matter in younger and older subjects were compared by Alzheimer’s disease (24– using t tests. Rates for other areas were compared by using two-factor repeated measures ANOVAs 27). Of note, in the older (with hemisphere as the repeated measure). Down’s syndrome subjects *p0.05) (figure 1). ing that the left hemisphere may be preferentially afAudiovisual stimulation. During audiovisual stimulafected early in Alzheimer’s disease (7). These findings tion, the older subjects showed significantly lower rates suggest that the accumulation of some degree or type of glucose metabolism in the inferior (F=7.2, df=1, 14, of Alzheimer’s disease neuropathology known to ocp=0.02), superior (F=19.6, df=1, 14, p=0.0006), and cur after age 40 years in Down’s syndrome results in medial (F=5.6, df=1, 14, p=0.03) parietal neocortical an impairment in the neuronal functional capacity to areas and in the insula (F=11.9, df=1, 14, p=0.004) and respond fully to stimulation, despite normal function sensorimotor (F=7.4, df=1, 14, p=0.02) regions. Global at rest. cerebral glucose metabolism also was significantly The absence of group differences in intellectual funclower in the older subjects with Down’s syndrome tion, cognitive status, or function of the peripheral audi(t=2.3, df=14, p=0.04). No significant difference was tory and visual systems suggests that these factors cannot observed in the other cerebral regions (figure 2). There explain the differences in regional cerebral glucose mewere no significant group-by-hemisphere interactions. tabolism between younger and older subjects with Down’s syndrome. Furthermore, 13 of the 16 subjects Changes in Cerebral Glucose Metabolism with Down’s syndrome in this study, including all eight in Response to Audiovisual Stimulation of the older adults, had been followed longitudinally and demonstrated no change over time in cognitive or behavMean changes in absolute cerebral glucose metaboioral functions and no sign of dementia (7). In contrast, lism between rest and audiovisual stimulation for both the onset of dementia in subjects with Down’s syndrome age groups are reported in table 2. The older adults is associated with a sharp linear decline of cognitive funcwith Down’s syndrome showed significantly smaller intions (7). Therefore, the lack of significant differences in creases for the superior temporal, insula, sensorimotor, cognitive measures between the two groups truly reflects and inferior parietal regions than the younger group. the absence of dementia in the older subjects with No significant group-by-hemisphere interactions were Down’s syndrome and cannot be ascribed to a low staobserved. tistical power due to the relatively small study group.

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Cerebral cortical atrophy also cannot exTABLE 2. Changes in Rates of Regional Cerebral Glucose Metabolism in Response to Audiovisual Stimulation for Younger and Older Adults With Down’s Syndrome plain the lower rates of regional cerebral glucose metabolism in the older subjects. Change in Metabolic Rate Repeated The effects of atrophy, if any, should re(mg/100 g of brain tissue per minute)a Measure sult in metabolic differences at rest beYounger Older Adults ANOVA tween the younger and older Down’s Adults (N=8) (N=8) (df=1, 14)b syndrome groups, which did not occur. Brain Region Mean SD Mean SD F p Further, older nondemented subjects with Down’s syndrome typically do not Orbitofrontal 0.2 n.s. Right 0.88 3.24 0.33 1.18 display greater cerebral atrophy than Left 0.70 2.10 0.44 1.27 young adults with Down’s syndrome (15). Prefrontal 0.7 n.s. The stimulation paradigm for this Right 1.23 1.31 0.96 1.44 study was selected to be an everyday acLeft 1.27 1.00 0.44 1.55 tivity (watching television) that could be Premotor 0.8 n.s. Right 1.42 1.34 1.39 1.51 reproduced easily in a PET scan environLeft 1.43 2.35 0.26 1.45 ment, to be of equal interest to both age Limbic 0.0 n.s. groups, and to require minimal compliRight 0.71 0.96 0.64 1.12 ance. The subjects were already familiar Left 0.40 0.60 0.59 1.03 Inferior temporalc 2.0 n.s. with the PET procedure because 13 had Right 1.89 2.30 0.76 0.84 previously had successful PET scans and Left 1.29 1.95 0.26 0.65 the remaining three had been trained Middle temporal 2.2 n.s. during the 2 weeks before the experiment Right 2.08 2.09 1.33 1.48 by having mock PET scans. This familiLeft 1.62 1.28 0.39 1.31 Superior temporal 5.2 0.04 arity and the simplicity of the experimenRight 2.74 2.36 1.38 0.76 tal design enabled them to comply fully Left 2.40 2.02 0.11 0.92 and attend to the task without anxiety. Insula 6.3 0.02 We continuously monitored the subjects Right 1.93 1.77 0.76 1.30 Left 2.09 1.44 –0.34 1.77 during the PET scan to ensure that they Sensorimotor 5.3 0.04 were actually attending to the movie durRight 1.52 1.09 0.86 1.09 ing the stimulation scan or were resting Left 1.15 0.99 –0.13 0.98 during the at-rest scan, without sleeping Inferior parietal 4.8 0.05 Right 1.69 1.19 1.09 0.77 or engaging in other activities, such as Left 1.87 1.36 0.53 0.68 talking. In addition, at the end of the Medial parietal 4.1 0.06 stimulation PET session, the younger Right 2.30 1.13 1.33 0.68 and older adults with Down’s syndrome Left 1.36 0.96 0.62 0.89 gave equally accurate answers to quesSuperior parietal 2.0 n.s. Right 0.96 1.02 0.84 1.00 tions about the movie. Thus, no differLeft 1.20 0.99 –0.01 1.32 ences in compliance or attendance to the Posterior cingulated 1.55 1.20 1.50 0.93 — — task can explain the abnormal brain reOccipitoassociation 1.2 n.s. sponse to stimulation in the older subRight 2.80 1.58 2.23 0.90 Left 2.94 1.72 2.17 1.08 jects with Down’s syndrome. Calcarine 1.1 n.s. One could argue that the aging process Right 4.14 3.19 3.16 1.20 per se rather than preclinical Alzheimer’s Left 3.86 3.73 2.62 1.38 disease could account for the metabolic Globale 1.75 1.06 1.03 0.72 — — impairments in the older subjects during aValue during stimulation minus value at rest. stimulation. The aging process in bWith hemisphere as the repeated measure. cdf=1, 13. Down’s syndrome, however, by definidPaired t test; t=0.1, df=14, n.s. tion is not a normal one, as Alzheimer’s ePaired t test; t=1.6, df=14, n.s. disease neuropathology invariably accumulates, thus making it impossible to distinguish the two processes (5, 6). Furobserved specifically in the parietal and temporal cortical thermore, in other groups of young and older healthy areas, regions that are affected early and almost invaripersons without Down’s syndrome (28), audiovisual ably in Alzheimer’s disease (23–27). stimulation was shown to enhance metabolic differences In summary, we believe that the differential increases across all the neocortical areas, with the greatest differin regional cerebral glucose metabolism reflect an intrinence occurring in the frontal lobes. The frontal cortical sic limitation of the brains of the older nondemented regions have been shown to be more susceptible to the adults with Down’s syndrome in responding to sensory effects of healthy aging (29). In contrast, the metabolic stimulation, as a result of preclinical Alzheimer’s disease. abnormalities associated with audiovisual stimulation in Prolonged audiovisual stimulation may act as a stressor the subjects with Down’s syndrome in this study were

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for the brain by requiring the neurons in multiple cortical and subcortical areas to increase activity in response to increased sensory input and associated information processing. Compared to the younger adults with Down’s syndrome, who have no or minimal accumulation of Alzheimer’s disease neuropathology, particularly in the neocortex, the older subjects with Down’s syndrome did not show the same degree of neuronal/synaptic response to stimulation, as measured by increases in regional cerebral glucose metabolism over at-rest values, suggesting that the accumulation of Alzheimer’s disease neuropathology results in an impairment of neuronal function. The use of the PET-FDG technique, in combination with a stimulus that acts like a stressor for the brain, may make it possible to uncover abnormalities in regional cerebral glucose metabolism that are not evident at rest. Despite the impairment of neuronal function during audiovisual stimulation, the older subjects with Down’s syndrome maintained nonmemory cognitive function similar to that of the younger subjects. This suggests that the brain is able to compensate to some degree for metabolic impairments during the stimulation of cognitive activity. Replication of our findings in another group of subjects at risk for Alzheimer’s disease, on the basis of family history or apolipoprotein E allele type, for example, is important. Recently, another group (30) examined subjects with mild memory complaints who were at risk for Alzheimer’s disease on the basis of family history and showed that those with the apolipoprotein E ε4 allele had lower rates of glucose metabolism in the parietal areas at rest than did subjects without the ε4 allele. Furthermore, Reiman et al. (31) showed abnormal patterns of glucose utilization at rest in the parietal, temporal, and prefrontal regions of cognitively normal subjects who were homozygous for the apolipoprotein E ε4 allele. Our study expands these results by showing that in an at-risk nondemented group with a 100% chance of developing substantial Alzheimer’s disease neuropathology and a high risk for subsequent clinical dementia, before the appearance of cognitive symptoms a brain stimulation paradigm can reveal cerebral metabolic abnormalities not seen at rest. Early identification of subjects at risk for Alzheimer’s disease may have important implications for the understanding of the neurobiological mechanisms involved in Alzheimer’s disease and for the selection of individuals who might benefit most from preventive or curative treatments once they become available (31). REFERENCES 1. Burger PC, Vogel FS: The development of pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome. Am J Pathol 1973; 73:457–476 2. Wisniewki KE, Wisniewki HM, Wen GY: Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985; 17:278–282 3. Haxby JV, Schapiro MB: Longitudinal study of neuropsychological function in older adults with Down syndrome, in Down Syndrome and Alzheimer Disease. Edited by Epstein C, Nadel L. New York, Wiley-Liss, 1992, pp 35–50

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